Development and Standardization of a Novel Pituitary Adenoma Organoid Model for the Study and Treatment of Cushing's Disease

用于研究和治疗库欣病的新型垂体腺瘤类器官模型的开发和标准化

基本信息

批准号：
10656854
负责人：
Andrew Scott Little
金额：
$ 43.98万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-05-25 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10656854
关键词：
Acceleration Adrenal Glands Anxiety Arizona Automobile Driving BRAF gene Biochemical CDH23 gene Cardiovascular Diseases Cell Culture Techniques Cell Differentiation process Cell Line Cell Lineage Cells Cellular biology Cessation of life Chemicals Chronic Clinic Confocal Microscopy Corticotropin Data Data Analyses Development Diabetes Mellitus Diagnosis Disease Disease remission Drug Screening Endocrine System Diseases Endocrinologist Exhibits Exposure to Flow Cytometry Funding Genes Goals Growth Health Hormone secretion Human Hydrocortisone Hypopituitarism Immune In Vitro Lead Link Malignant Neoplasms Medical Mental Depression Modeling Molecular Profiling Morphology Mus Mutation Neuroendocrine Tumors Neurologic Neurosurgeon Obesity Operative Surgical Procedures Organoids Pathogenesis Pathologic Pathology Patient-Focused Outcomes Patients Pharmaceutical Preparations Pituitary Diseases Pituitary Gland Pituitary Gland Adenoma Pituitary Neoplasms Pituitary-dependent Cushing&apos s disease Population Positioning Attribute Pre-Clinical Model Production Proliferating Quality of life Radiosurgery Rattus Recurrence Recurrent disease Recurrent tumor Research Resected Resistance Risk Route Signal Pathway Standardization Stroke Stromal Cells Study models Surgeon Technology Therapeutic Time Tissues Training Translating Tumor Pathology Tumor Subtype Tumor-Derived USP8 gene Universities adenoma clinical practice digital drug repurposing effective therapy experience follow-up illness length improved induced pluripotent stem cell mortality risk nano-string novel novel therapeutic intervention patient tolerability prevent response screening standard of care stem stem cells targeted treatment therapy development three dimensional cell culture tissue/cell culture transcriptome transcriptomics tumor

项目摘要

PROJECT SUMMARY/ABSTRACT Cushing’s disease (CD) is a serious endocrine disorder characterized by an adrenocorticotropic hormone (ACTH)-secreting PitNET that subsequently stimulates the adrenal glands to overproduce cortisol. Chronic exposure to excess cortisol has wide ranging and detrimental effects on health, including increased stroke rates, diabetes, obesity, depression, anxiety and death. Although CD is linked to a threefold increase in the risk of death, the advancement of current standard of care medical therapy is lacking. Current treatments exhibit low efficacy and tolerability for patients. The absence of preclinical models that replicate the complexity of the adenoma tissue has prevented us from developing effective therapies that are targeted to the tumor directly. The first-line treatment for CD is pituitary surgery. In the hands of an experienced surgeon, tumor recurrence occurs in as many as 30% to 50% of patients during the 10-year follow-up period. Despite multiple treatments, biochemical control is not achieved in approximately 50% of patients, suggesting that in routine clinical practice, initial and long-term disease remission is not achieved in a substantial number of CD patients . Hence, medical therapy is often considered in the following situations: when surgery is contraindicated or fails to achieve remission, or when recurrence occurs after apparent surgical remission. While stereotactic radiosurgery treats incompletely resected or recurrent PitNETs, the main drawbacks include the longer time to remission and the risk of hypopituitarism. There is an inverse relationship between disease duration and reversibility of complications associated with CD, thus emphasizing the importance of targeting the pituitary adenoma early. The primary barrier to developing new medical therapies is the lack of human relevant advanced in vitro tumor models. Pituitary cell lines do not reproduce the multicellular complexity of PitNETs. In this instance, the overall objective is to develop PitNET organoids to advance our understanding of the pathogenesis and treatment of pituitary tumors in CD patients. The overall goal will be successfully achieved by collaborative efforts between the University of Arizona (UA) and Barrow Neurological Institute (BNI) that will leverage the expertise of professionals trained in complimentary fields including surgical treatments, pathology and cell biology of pituitary disease, organoid technology and high throughput data analysis including dug screening, molecular profiling, and transcriptomics. This led us to develop Specific Aims: 1) To use human PitNET derived organoids to define the molecular signatures of corticotroph tumor subtypes in CD, and 2) To use the pituitary tumor organoids as a preclinical model to accelerate targeted therapies for patients with CD. At the completion of the funding period, we will be positioned to implement patient-relevant organoids to accelerate the development of therapies that will effectively target ACTH-secreting pituitary adenomas in patients with CD.

项目概要/摘要库欣病（CD）是一种严重的内分泌疾病，以促肾上腺皮质激素为特征 (ACTH) 分泌 PitNET，随后刺激肾上腺过度产生慢性皮质醇。接触过量的皮质醇会对健康产生广泛的破坏性影响，包括增加中风率、尽管 CD 与糖尿病、肥胖、抑郁、焦虑和死亡的风险增加三倍有关。死亡，目前的护理医疗水平缺乏进步，目前的治疗水平较低。缺乏复制复杂性的临床前模型。腺瘤组织阻碍了我们开发直接针对肿瘤的有效疗法。 CD 的一线治疗是垂体手术，在经验丰富的外科医生手中，肿瘤会复发。尽管进行了多次治疗，但在 10 年随访期间仍有多达 30% 至 50% 的患者出现这种情况。大约 50% 的患者未实现生化控制，这表明在常规临床实践中，大量 CD 患者未能实现初始和长期疾病缓解，因此需要进行医疗治疗。在以下情况下通常会考虑治疗：当手术有禁忌症或无法达到手术目的时缓解时，或在立体定向放射外科治疗时明显手术缓解后出现复发时。不完全切除或复发的 PitNET，主要缺点包括缓解时间较长和垂体功能减退症的风险与疾病持续时间和可逆性呈反比关系。与 CD 相关的并发症，因此强调了早期针对垂体腺瘤的重要性。新医学疗法的主要障碍是缺乏人类相关的先进体外肿瘤开发垂体细胞系不能再现 PitNET 的多细胞复杂性。目标是开发 PitNET 类器官，以增进我们对疾病发病机制和治疗的理解通过双方的共同努力，总体目标将成功实现。亚利桑那大学 (UA) 和巴罗神经病学研究所 (BNI) 将利用受过免费领域培训的专业人员，包括垂体的手术治疗、病理学和细胞生物学疾病、类器官技术和高通量数据分析，包括挖掘筛选、分子分析、这导致我们制定了具体目标：1）使用人类 PitNET 衍生的类器官来定义 CD 中促肾上腺皮质激素肿瘤亚型的分子特征，以及 2) 使用垂体肿瘤类器官作为加速 CD 患者靶向治疗的临床前模型。我们将致力于实施与患者相关的类器官，以加速开发治疗方法将有效针对 CD 患者中分泌 ACTH 的垂体腺瘤。